Dopamine neurotransmission is important for many physiological functions and its dysregulation contributes to numerous neurological disorders. Previously, we showed that the neuronal protein kinase Cdk5 modulates dopamine efficacy by converting the striatal phosphatase inhibitor DARPP-32 into a PKA inhibitor. Further studies of the regulation of dopamine signaling by Cdk5 using pharmacology and transgenic technology have revealed novel mechanisms by which Cdk5 is likely to govern PKA activity in the striatum. Here we provide evidence that Cdk5 regulates PKA through phosphorylation of the PKA holoenzyme RII2 subunit. Furthermore, Cdk5 regulates intracellular cAMP levels through direct phosphorylation the phosphodiesterase PDE4B or controlling its regulation by PKA and MAPK. We made conditional Cdk5 knockout models and found that knockout in adult mice results in severe alterations in dopamine signaling. We propose to further study Cdk5- dependent regulation of PKA signaling pathways in striatal neurons using a conditional knockout approach. We propose to characterize the biochemical mechanisms by which Cdk5 regulates PKA both in vitro and in intact striatal tissue. These studies will identify targets and suggest strategies for the development of new treatments for neurological and neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: Neuropsychiatric disorders that are caused by disruptions in dopamine neurotransmission include schizophrenia, attention deficit hyperactivity disorder, and numerous other mental illnesses. The goal of this research is to delineate new mechanisms by which dopamine neurotransmission is regulated involving the neuronal protein kinase Cdk5 so that new pharmacotherapeutic treatments for these disorders can be developed.